Purified microvascular endothelial cell preparations from guinea pig fat pad, heart, and brain were found to contain high histamine methyltransferase (HMT) activity. These cells appeared to account for most of the HMT activity in the whole fat pad, whereas in heart and brain the enzyme was not restructed to endothelial cells. The myocyte, for example, was an additional source of HMT activity in heart. HMT activity in the endothelial cells from fat pad and heart was the highest found so far in quinea pig tissues. In rat, a species in which diamine oxidase (DAO) is the major degradative enzyme for histamine, HMT activity was approximately 1% of that in the same preparations from guinea pig. DAO activity in the microvascular cell preparations from both species was 5 to 40 times than in the parent tissues. In addition to their ability to degrade serotonin and catecholamines, the microvascular endothelial cells may be an important site of inactivation of circulating histamine.